CHRDL2 mediates muscle–liver crosstalk linking sarcopenia and metabolic dysfunction-associated steatotic liver disease

Sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexist in older adults, yet the mechanisms underlying their shared pathogenesis remain unclear. Linkage disequilibrium score regression, multi-trait genome-wide association meta-analysis, transcriptome- and proteome-wide association studies, and Mendelian randomization were integrated to delineate the shared genetic architecture of sarcopenia-related traits and MASLD and identify potential mediators of muscle–liver crosstalk. Murine and cellular models, conditioned-medium transfer experiments, Chrdl2 knockdown, BMP signaling rescue experiments, structure-based virtual screening, molecular dynamics simulations, biophysical and pharmacological validation were subsequently used to establish the biological role, underlying mechanism, and therapeutic tractability of CHRDL2. Significant genetic correlations were observed between sarcopenia-related traits and fatty liver disease, and 13 shared loci were identified, implicating BMP/TGF-β signaling and metabolic pathways. Integrated analyses prioritized chordin-like 2 (CHRDL2), a secreted BMP antagonist, based on significant transcript- and protein-level associations, while Mendelian randomization supported causal effects of circulating CHRDL2 on both sarcopenia and fatty liver disease. Across murine and cellular models, CHRDL2 was markedly upregulated in sarcopenic skeletal muscle and aging-like myotubes but not in steatotic liver or hepatocytes. Recombinant CHRDL2 induced myotube atrophy and lipid accumulation in hepatocytes. Conditioned medium from D-gal-treated myotubes recapitulated both phenotypes, whereas Chrdl2 knockdown markedly attenuated them, supporting CHRDL2 as a mediator of muscle–liver crosstalk. Mechanistically, these effects were mediated by suppression of BMP/SMAD signaling. Structure-based screening identified cinacalcet hydrochloride as a potential CHRDL2-binding compound, and molecular dynamics simulations and biophysical experiments suggested that cinacalcet binding destabilized CHRDL2. Consistently, cinacalcet reduced CHRDL2 protein levels and ameliorated muscle atrophy and hepatic lipid dysregulation in vitro and in vivo. These findings identify CHRDL2 as a pathogenic mediator of muscle–liver crosstalk linking sarcopenia and MASLD through suppression of BMP/SMAD signaling and support targeting CHRDL2 as a potential therapeutic strategy for these coexisting disorders.